Basic salicylamides



United States Patent 2,810,718 BASIC SALICYLAMIDES Bruce W. Horrom andLeo'R. Swett, Waukegan, 111., as-

signors to Abbott Laboratories, North Chicago, Ill., a corporation .of-Illinois No Drawing. Application July 2, 1953, Serial No. 365,768

19 Claims. (Cl. 260-4473) This invention relates to a class of newchemical compounds identified'broadly as the basic salicylamides and thebasic acetylsalicylamides. The invention further relates to a novelmethod for making such new chemical compounds.

The new chemical compounds of this invention show activity as localanesthetics and fungicides. In addition the basic salicylamide chemicalstructure is of considerable general interest in the pharmaceuticalfield and mnnerous. attempts have been made in the .past to.-synthe.size new chemicals of this general vtype, without 'success. hisnow. possible through the practice of this invention to prepare newchemicals which may be identifiedbyithe formula where R is from thegroup consisting of hydrogen and acetyl, X is from the group consistingof substituted piperazyl, substituted piperidyl and :where' R isf-romthe group consisting of hydrogen and lower alkyl, Y is from the class.consisting of alkylene groups having 2-10 carbon atoms and saturatedcyclic :the methyl, ethyl, propyl, butyl' groups and branched chain:equivalents. "The symbol Y is intended to include straight.andhranchedichain alkylene groups as well as'cyclic :groups, such asthecyclohexyl derivative of Example X. .The substituted piperaz'ine andsubstituted piperidine groups which are designated by the symbol X inthe foregoing formula are those'piperazine's and piperidines which aresubstituted by an alkyl group or a substituted alkyl group. Forexamplethe substitution may be of a methyl, ethyl, propyl, or butyl group inone or more of the positions on the ring compound. As substituted alkylgroups may be mentioned, the piperidinoethyl group, the morpholinoethylgroup, thedialkylaminoethyl group, the carbethoxy group and equivalentchemical structures.

The compounds of this invention are made by reacting equirnolarproportions of an acetylsalicylyl halide and a diamine from the groupconsisting of substituted piperazyl,

substitutedtpiperidyl and Patented Oct. 22, 1957 'ice where R1 ishydrogen or lower alkyl, Y is an alkylene chain of 2 to 10 carbons or asaturated cyclic hydrocarbon group of 2 to 6 carbons :and ,R2 is,dialkylamino, 'piperidino or morpholino. The reaction is carried out atlow temperatures (ice bath) in the presence of ether. A water solubleproduct is formed which is extracted with a large volume of ether.Substantially all of the ether must then be removed, as by filtrationthru a'fine sintered glass funnel, with the aid of a high vacuum pump.Thereafter a basic salicylamide is obtained either in the form of an oilor as a crystallized product. The acetyl group may be removed byhydrolysis using an alkali to give the phenolic basic amide.

The following examples are presented in order to disclose the inventionmore fully. *It should be understood however that the examples are notintended in any way to be a limitation of the invention.

7 EXAMPLE I N-fl-morpholinoethylacetylsalicylamide To a stirred.solution of 19.8 g. (.1 mole) of acetylsalicylyl chloride in 300 cc. ofether, which is cooled in an ice bath, there is added dropwise asolution of 13.0 g. (.1 mole) of N-morpholinoethylaminein 100 cc. ofether. After. the addition is completed, the mixture is allowed tocometo' room temperature and is stirred for six hours. The hydrochloride,is filtered off and dried in a vacuum dessicator, to give 26 g. of avery hygroscopic material. This is recrystallized from ethanol-ether togive 22.5 g. of the above named product, M. P. 147-150 C.; a yield of69%. Further recrystallization raised the melting point to l50l52 C.Analysis.-Calc. for C15H20N204.HC12 C,'54.79; H,-6.44; N, 8.52. Found:C, 54.81; H, 6.33; N, 8.40.

EXAMPLE II N- (2-dimethylamino-Z-methylpropyl) -acetylsalicylamide OO-PJ-CH: i CH3 To a stirred solution of 19.8 g. (.1 mole) ofacetylsalicylyl chloride in 300 cc. of ether, which is cooled in an icebath, there is added dropwise a'solution of 11.6 g. (.1 mole) ofZ-dimethylamino-Z-methylpropylamine in 100 cc. of ether. After theaddition is completed, the mixture is allowed to come to roomtemperature and is stirred for six hours. The -hydrochloride (22 g.) isfiltered off but is too hygroscopic to work with. It is dissolved inwater, cooled and neutralized with 10% sodium hydroxide solution. Thebasic solution is continuously extracted with ether for twenty-fourhours and the ether portion dried over anhydrousmagnesium sulfate. Theether mixture is then filtered and the solvent removed in vacuo, toleave a viscous oil residue. The oil is filtered through a fine sinteredglass funnel with the aid of a high vacuum pump to remove the lasttraces of solvents. Upon standing the above named material crystallizes.There is obtained 10.7 g. M. P. 100 C. Recrystallization from etherraises the melting point to 101-103 C.; yield 39%. Analysis.-Ca1c. 'forC15H22N203I C, 64.72; H, 8.15. Found: C, 64.96; H,-8.36,

"as a very viscous yellow oil.

, By the procedure of Example H using 11.4 g. (.1 mole) V .of1,2-dimethylpiperazine, there isobtained 1,2-dimethy1- 7 1 e e 1 By theprocedure of Example Husing 18.6 g. (.1 mole) V V ofN-carbethoxy-2,6-dimethylpiperazirie, there is obtained V Found; C,65.39.;1HuZ-56. l 1 7 i 6.6 g. 'sarhple ofN-B-rnorpholinoethylacetylsalicylj amide hydrochloride is dissolvedinwater'and rnade valkaline with %'sodium hydroxidessolutiou. The basicEXAMPLE IV N-(i-dilizethylaminopropyl-Z)-acetylsalicylamide oil-0H.

(EH3 /CH: enyon-ea n g .Bythe procedure of Example II using 10.2 g.'( .1mole) of 1-methyl-2-dimethylaminoethylamine, there 'is .ob- 'tained'N-(l-dimethylaminopropyl-2)-acetylsalicylamide Analysis.Calc. forCHI-120N203: C, 63.61;'H, 7.63. Found: C, 63.47; H,

V EXAMPLEV 7 N-methyl-N-fl-dirfiethylaminoethylacetylsdlicylamide O 4o OCHa V |CIIT-CHz0Ha-N 7 V (.J) CH3 CH3 By the procedure of Example 11using 10.2 g. (.1 mole) of eN-methyl-,B-dimethylaminoethylamine, thereis obtained N-methyl {N 3 dimethylaminoethylacetylsalicyl- .arnide as alight yellow viscous oill- Ana Zysis.Calc. for ZC1 4H20N203: C, 63,61;H, 7.63. Found: C, 63.75; H, 7.51. I I r i V EXAMPLE VI" r a1,2-iiimethyl-4 acetylsalicyloylpiperezine Oil-e11. om

C'N' I}; N-CH 0 IL 4-acetylsalicyloylpiperazine as .a lightyellowviscous oil. ginalysisr Calc. -for .CI5H20N2O3IVI C, 65.19; H,..7.30.

IV-,8-dirnet '1;ylaminoezhylacetylsalicylainirie '1 1 7 f Bythe'procedure of Example II using 9 g. (.1-mole) V I J ofdimethylaminoethylamine, there is obtained N-fldimethylarninoethylacetylsalicylamide 'as a straw colored By theprocedure of Example llusing 10 g. (.1 mole) of N-methylpiperazine,there is 7, obtained .1-methyl-4 acetylsalicyloylpiperazine, M. P.133135 C. "An?!- ysis.-Calc.f or C14H18N203; N, 13.08. Found: N, 12.95.

' EXAMPLE X o-4-cyclohexyl)-aciylsalicylam V N-(l-ziz'ethyl amin ide ABy the procedure of Example ll-us ing l lg; 111161; ofN,N-diethyI-1,4rcyclohexanediamine, there'is obtained N (1 diethylamino4 cyclohexyl) t-acetylsalicylamide,

M. P. 98-99 C. Analysis.Calc. for vCmHmsNzOa':

c, 68.64; H, 8.49; N, 8.43. FoundzC, 68.84;H, 8.37;

r EXAMPLEH 1 e l-cqrlvethoxy-4-acetylsalicyloylpiperaiine A V 0 (Pg-0H;

1-carbeth0xy-4-acetylsalicyloylpiperazine as .a colorless viscous oil.Analysis.Ca1c. for Ciel-120N205: C, 62.05; H, 6.94; N, 8.04. Found: C,61.96; H, 7.07; N, 7.89.

EXAMPLE XII N-methyl-N-p-piperidinoethylacetylsalicylamide ll OC-CH3-ONCHz-CHz-N' H CH By the procedure of Example II using 14.4 g. (.1mole) of N-methyl-B-piperidinoethylamine, there is obtainedN-methyl-N-fl-piperidinoethylacetylsalicylamide as a viscous oil.Analysis.Calc. for C17H24N2032 C, 67.08; H, 7.95; N, 9.21. Found: C,66.50; H, 7.85; N, 8.84.

EXAMPLEPGII N-B-morpholinopropylsalicylamide O -N HOH2-OH2 CH2-N 2) L/By the procedure of Example II followed by the procedure of Example III,using 14.4 g. (.1 mole) of 6rnorpho1in0propy1arnine, there is obtainedN-fi-morpholinopropylsalicylamide as colorless plates, M. P. 8081 C.Analysis.Calc. for C14H20N2O3: C, 63.61; H, 7.62; N, 10.60. Found: C,63.79; H, 7.47; N, 10.70.

EXAMPLE XIV N-e-morpholinopentylsalicylamide 6 We claim: 1. A newchemical compound selected from the group consisting of bases having theformula where R is selected from the group consisting of hydrogen andacetyl and n is 25 inclusive, and the acid addition salts thereof.

2. A base having the formula where n is 2-5.

3. The bases according to claim 1. 4. The acid addition salts accordingto claim 1. 5. A base having the formula where n is 25 inclusive.

6. N-e-morpholinopentylsalicylamide.

7. N-'y-morpholinopropylsalicylamide.

8. N-fl-morp'holinoethylacetylsalicylamide ride.

9. N-p-morpholinoethylsalicylamide.

hydrochlo- References Cited in the file of this patent UNITED STATESPATENTS 2,338,178 Graenacher et a1 Jan. 4, 1944 2,419,932 Grimmel et a1.Apr. 29, 1947 2,464,094 Meade Mar. 8, 1949 2,688,026 Krimmel Aug. 31,1954 2,690,041 Clinton Oct. 5, 1954 2,691,025 Clinton Oct. 5, 1954 OTHERREFERENCES Conant et al.: Chemistry of Organic Compounds, pages 97-98,1947.

Bing et a1.: Acta Phar., vol. 4, pp. 199-204 (1948).

1. A NEW CHEMICAL COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASESHAVING THE FORMULA